Chemotherapy forms the backbone of modern treatment for infectious diseases by using chemical agents to selectively destroy or inhibit pathogenic microorganisms. From the early discovery of sulfonamides to the development of advanced antibiotics, chemotherapy has dramatically reduced mortality and improved quality of life across the globe. Unit 2 focuses on the general principles of chemotherapy and provides an overview of key antimicrobial drug classes used in clinical practice.
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General Principles of Chemotherapy
Concept and Objectives
Chemotherapy refers to the treatment of diseases using chemical substances that exhibit selective toxicity, meaning they harm invading microorganisms without causing significant damage to the host. The primary objective is to eradicate the pathogen while minimizing adverse effects on human cells.
Selective Toxicity and Therapeutic Index
An ideal chemotherapeutic agent should have high selective toxicity. This property is measured by the therapeutic index, which compares the toxic dose to the effective dose. Drugs with a higher therapeutic index are safer and more desirable for clinical use.
Bactericidal vs Bacteriostatic Agents
Chemotherapeutic agents are classified as bactericidal, which kill microorganisms directly, or bacteriostatic, which inhibit their growth and rely on the host’s immune system for elimination. The choice depends on the severity of infection and immune status of the patient.
Spectrum of Activity and Resistance
Antimicrobials may be narrow-spectrum or broad-spectrum. While broad-spectrum drugs are useful in mixed infections, their overuse can lead to antimicrobial resistance, a major global health concern. Rational drug use and combination therapy help delay resistance development.
Sulfonamides and Cotrimoxazole: The Pioneers of Chemotherapy
Sulfonamides
Sulfonamides were the first effective systemic antibacterial agents. Chemically, they are structural analogues of para-aminobenzoic acid (PABA) and inhibit bacterial folic acid synthesis. By blocking dihydropteroate synthase, they prevent the formation of nucleic acids essential for bacterial growth.
Therapeutic Applications
Sulfonamides are effective against urinary tract infections, respiratory infections, and some gastrointestinal infections. However, their use has declined due to resistance and adverse effects such as hypersensitivity reactions and crystalluria.
Cotrimoxazole
Cotrimoxazole is a fixed-dose combination of sulfamethoxazole and trimethoprim. This combination produces a synergistic effect by sequentially blocking folic acid synthesis at two different steps. Cotrimoxazole is widely used for urinary tract infections, respiratory infections, and opportunistic infections such as Pneumocystis pneumonia.
Antibiotics: Major Classes Used in Chemotherapy
Penicillins
Penicillins are β-lactam antibiotics that inhibit bacterial cell wall synthesis by blocking transpeptidase enzymes. This leads to cell lysis and death, making them bactericidal. Penicillins are widely used due to their effectiveness and relatively low toxicity, though allergic reactions and resistance are common concerns.
Cephalosporins
Cephalosporins are structurally related to penicillins but exhibit greater resistance to β-lactamases. Classified into generations, they show progressive improvement in gram-negative coverage and stability. They are commonly used in respiratory, urinary, and systemic infections.
Chloramphenicol and Macrolides
Chloramphenicol
Chloramphenicol is a broad-spectrum antibiotic that inhibits protein synthesis by binding to the 50S ribosomal subunit. Despite its effectiveness, its use is restricted due to serious adverse effects such as aplastic anemia. It is now reserved for severe infections when safer alternatives are unavailable.
Macrolides
Macrolides such as erythromycin, clarithromycin, and azithromycin inhibit bacterial protein synthesis by acting on the 50S ribosomal subunit. They are particularly useful in respiratory tract infections and in patients allergic to penicillins. Improved derivatives offer better acid stability and tissue penetration.
Quinolones and Fluoroquinolones
Mechanism and Spectrum
Quinolones act by inhibiting bacterial DNA gyrase and topoisomerase IV, enzymes essential for DNA replication. Fluoroquinolones, which contain a fluorine atom, have enhanced potency and broader antimicrobial spectrum.
Clinical Uses
These agents are widely used in urinary tract infections, gastrointestinal infections, and respiratory tract infections. Their excellent oral bioavailability makes them suitable for both outpatient and inpatient therapy.
Tetracyclines and Aminoglycosides
Tetracyclines
Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis by binding to the 30S ribosomal subunit. They are effective against atypical organisms, rickettsial infections, and acne. Limitations include gastrointestinal irritation and effects on developing teeth and bones.
Aminoglycosides
Aminoglycosides such as gentamicin and streptomycin are bactericidal antibiotics that inhibit protein synthesis by irreversible binding to the 30S ribosomal subunit. They are particularly effective against gram-negative bacteria but require careful monitoring due to nephrotoxicity and ototoxicity.